LIN-35/Rb Causes Starvation-Induced Germ Cell Apoptosis via CED-9/Bcl2 Downregulation in Caenorhabditis elegans

Abstract

Apoptosis is an important mechanism for maintaining germ line health. In Caenorhabditis elegans, germ cell apoptosis occurs under normal conditions to sustain gonad homeostasis and oocyte quality. Under stress, germ cell apoptosis can be triggered via different pathways, including the following: (i) the CEP-1/p53 pathway, which induces germ cell apoptosis when animals are exposed to DNA damage; (ii) the mitogen-activated protein kinase kinase (MAPKK) pathway, which triggers germ cell apoptosis when animals are exposed to heat shock, oxidative stress, or osmotic stress; and (iii) an unknown mechanism that triggers germ cell apoptosis during starvation. Here, we address how starvation induces germ cell apoptosis. Using polysomal profiling, we found that starvation for 6 h reduces the translationally active ribosomes, which differentially affect the mRNAs of the core apoptotic machinery and some of its regulators. During starvation, lin-35/Rb mRNA increases its expression, resulting in the accumulation of this protein. As a consequence, LIN-35 downregulates the expression of the antiapoptotic gene ced-9/Bcl-2. We observed that the reduced translation of ced-9/Bcl-2 mRNA during food deprivation together with its downregulation drastically affects its protein accumulation. We propose that CED-9/Bcl-2 downregulation via LIN-35/Rb triggers germ cell apoptosis in C. elegans in response to starvation. Many germ cells (known in many organisms as nurse cells) are needed to produce a single oocyte. Once they have served their purpose, nurse cells are eliminated by apoptosis. An unsolved question in the germ cell field is how apoptosis is triggered to produce and sometimes protect germ cells. Adult Caenorhabditis elegans nematodes that encounter food deprivation enter a diapause stage that allows them to survive for a few months and put off fertility (1, 2). Later, when animals are subjected to better conditions, they exit adult diapause and restore fertility. Germ cell apoptosis is a key element to protect gonads from starvation, as exhibited by mutants of the caspase CED-3 that are unable to restore fertility after adult diapause (1). Previously, we found that starvation triggers germ cell apoptosis (3), and in this study we proposed a model to explain how this response is regulated in C. elegans.In C. elegans, apoptosis occurs in somatic tissues during embryonic and postembryonic development (developmental apoptosis) (4, 5) and in the adult hermaphrodite gonad (physiological germ cell apoptosis) (6). In this nematode, apoptosis is executed via a conserved pathway that consists of the proteins CED-3 (a caspase), CED-4 (APAF1-like adaptor protein), and CED-9 (BCL2 ortholog) (reviewed in references 7 and 8). Developmental apoptosis is initiated when the protein EGL-1 (BH3-only) disrupts the CED-9/CED-4 complex, thereby triggering CED-3 activation.The mechanism that induces physiological germ cell apoptosis is independent of EGL-1 (6) and is partially induced by the ortholog of the human retinoblastoma gene (Rb) lin-35, which...

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